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Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists

revised on 24.08.2020, 03:45 and posted on 24.08.2020, 07:24 by Sheng Zhang, Maj Krumberger, Michael A. Morris, Chelsea Marie T. Parrocha, James H. Griffin, Adam Kreutzer, James S. Nowick
This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information (supplementary material) provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.


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University of California, Irvine


The United States of America

ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflict of interest.